Device and mixing and/or reconstitution method

ABSTRACT

The disclosure refers to a device, for example a cartridge, a syringe or an autoinjector, which reduces the possibility of user error and provides an easy and automatic operation during mixing and/or reconstitution. The device is adapted such that activation of the device causes movement one of a first piston and a second piston in second chamber in an axial direction of the device, thereby moving the other one of the first piston and the second piston into the same axial direction of the device, opening a fluid communication path between the second chamber and a first chamber of the device, and expelling a second material from the second chamber into the first chamber via the fluid communication path. The disclosure is further directed to a respective mixing and/or reconstitution method.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national stage entry of InternationalPatent Application No. PCT/EP2018/081375, filed on Nov. 15, 2018, andclaims priority to Application No. EP 17306598.8, filed on Nov. 17,2017, the disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The disclosure refers to a device, particularly an injection device, anda mixing and/or reconstitution method.

BACKGROUND

Certain drugs are ideally administered in a liquid form, injectedsubcutaneously for the optimal therapeutic effect. However, some ofthese liquid drugs are unstable, having a shelf live that is relativelyshort. This can be a problem both for prophylactic treatments, wherepatients must inject themselves on a regular basis and therefore want tokeep a reasonable supply of drug at home, and for emergency treatments,where patients need to keep a supply of the drug to hand but may notneed it for weeks or longer.

In this case often drugs in a concentrated liquid form or lyophilized(freeze-dried) drugs are used, which usually comprise separatecomponents, namely a powder or liquid which is much more stable andtherefore has a long shelf life, and a diluent liquid. These componentsare typically supplied in separate vials and the user must reconstitutethe drug prior to injection. Such reconstitution is often a complexprocess with many steps. Also, there is the risk during thereconstitution process at various points that, if the user is notcareful, the drug can be contaminated. Therefore, there is a need for asystem and a method which removes the possibility of user error andprovides a well reconstituted and/or mixed drug in a short time.

From document US 2013/0296807 A1 a device for automatic reconstitutionand delivering a drug to a user and a method thereof is known. There isa need for a system or injection device which reduces the possibility ofuser error and provides an easy and automatic operation.

SUMMARY

In certain aspects, a medical device or a method is provided.

In one aspect, the device comprises

-   -   a housing,    -   a first chamber within the housing, wherein the first chamber        contains a first material,    -   a second chamber comprising a first piston and a second piston,        wherein the first piston and the second piston are axially        moveable within the second chamber, and    -   a second fluid material initially contained within the second        chamber between the first piston and the second piston,

wherein the device is adapted such that activation of the device causesmovement one of the first piston and the second piston in an axialdirection of the device thereby

-   -   moving the other one of the first piston and the second piston        into the same axial direction of the device,    -   opening a fluid communication path between the second chamber        and the first chamber and    -   expelling the second material from the second chamber into the        first chamber via the fluid communication path.

The present disclosure particularly refers to the mixing and/orreconstitution of a first drug component formed by or contained withinthe first material and a second drug component formed by or containedwithin the second material. Reconstitution is the rehydration of alyophilized (freeze dried) drug (e.g. first drug component) by a diluent(e.g. second drug component). The term mixing refers to any otherintermixing of any first and second drug component.

In some aspects, the advantage of the device may consist therein thatthat it provides improved and easy user operability because the userneeds only to pull back the plunger until it naturally snaps back intothe injection device. Then, the mixing and/or reconstitution is/areautomatically effected after fluid communication between the first andthe second chamber is established. After mixing and/or reconstitution avisual check of mix clarity is needed before the mixed and/orreconstituted drug comprising the first drug component and the seconddrug component can be injected.

In one embodiment the first material is a fluid or a solid material, forexample, a first drug component e.g. a solid drug component, preferablya lyophilized drug, and the second fluid material is, for example, asecond drug component e.g. a fluid drug component, preferably a diluent.

According to some aspects, the device is a cartridge, a syringe, or anautoinjector; or a combination of either one of a syringe or anautoinjector (also referred to as unit in the following) with acartridge or a primary package attached to the distal end of theautoinjector or syringe.

In one embodiment a needle may be attached at a distal end of thehousing. The needle is in fluid communication with the first chamberaccommodated within the housing. The needle is preferably covered at itsdistal end by a needle boot. This prevents air from being drawn into thedevice, in particular as the plunger is pulled.

In one embodiment the first piston and the second piston close thesecond chamber at its proximal and distal end, respectively.

In a further embodiment the movement of the one piston of the first andsecond piston drives the other one of the first and second piston viathe second material accommodated between the first piston and the secondpiston, i.e. the second material is the pressure transfer medium.

In a further embodiment the second material mixes and/or reconstituteswith the first material within the first chamber. Alternatively, thesecond material mixes and/or reconstitutes with the first materialwithin the second chamber.

In another embodiment the other one of the first piston and the secondpiston comprises a needle which pierces a seal or membrane when movedinto the axial direction in order to open the fluid communication pathbetween the second chamber and the first chamber.

In an alternative embodiment the plunger further comprises a (e.g.cylindrical) through hole at its distal end closed by a plug (e.g. acotter pin) which is connected with the second piston, wherein the innersurface of the plunger and/or the through hole and/or the outer surfaceof the plug comprises web-like elements dimensioned such that afteractivation of the device by pulling the plunger, e.g. in proximaldirection, the second piston moves into distal direction relative to theplunger such that the web-like elements (e.g. longitudinal ribs)counteract with the plug and/or the inner surface of the through holeand/or the plunger thereby creating the fluid communication path betweenthe second chamber and the first chamber and expelling the second drugcomponent into the first chamber. For that the second piston and/or thethrough hole has a compressible outer or inner surface, respectively.The plug (cotter pin) may be formed as a stud-like element. The plug maybe rigidly connected with the second piston.

Pulling the plunger into proximal direction causes a pressure dropwithin the device, e.g. in the first chamber and/or the second chamber.In one embodiment the pressure drop is first caused in the first chamberand then, after establishing fluid communication between the firstchamber and the second chamber, a decrease in pressure occurs in thesecond chamber. In one embodiment the pressure drop in the first chambermay create a force on the second piston that forces the plug (which isconnected with the second piston) to move through the through hole ofthe plunger.

In one embodiment the pressure difference inside the first chamber andthe second chamber may create a force on the second piston. This forcemay be transferred through the second drug component contained in thesecond chamber and onto the first piston. The plug may thereby be movedthrough the through hole and, accordingly, the second piston until thefirst piston hits the second piston. The plug and/or the second pistonmay comprise a compressible outer surface which may interact with a setof web-like elements (longitudinal ribs) that may be provided at thedistal end of the inner surface of the plunger forming an uneven innersurface. When the plug connected to the second piston is pushed into theuneven area (ribs) the initially formed seal may be broken. These ribsmay force gaps to open up around the second piston and fluid can gothrough and therefore may open a fluid communication path between thesecond drug component contained in the second chamber and the first drugcomponent contained in the first chamber via the through hole. Thesecond drug component flows out the distal end of the plunger and intothe first chamber of the device. In one embodiment all of the seconddrug component will have passed into the first chamber of the syringebefore the plunger is pulled back completely.

Additionally, the drive mechanism is held in place by a clip feature.The clip feature may comprise a spring. A cap on the distal end of thedevice or the primary packaging (explained below) may sit over the clipfeature, i.e. the cap covers the clip feature. When the cap is pusheddownwards or pulled, e.g. into proximal direction, it may release theclip mechanism and allow the spring to apply an axial force intoproximal direction to the first piston, to the second piston or theplunger.

In a further embodiment the device of any of the previous claims furthercomprises a plunger which closes a proximal end of the first chamberwithin the housing, wherein the plunger contains the second chamber,wherein the plunger is axially moveable within the housing of thedevice, wherein axial movement of the plunger within the housing, e.g.pulling into proximal direction, activates the device. In order to pullback the plunger, alternatively, a combined axial and rotational(twisting) motion may be conducted by the user.

In one embodiment the plunger comprises a handle at its proximal end foreasy operation.

In other embodiments a non-return mechanism between plunger and housingprevents the plunger from moving back into the syringe until it hasmoved through its full proximal stroke, e.g. comprising a ratchet trackprovided in one axial direction (activation direction, e.g. proximaldirection) and a smooth return track in the opposite axial direction. Inone embodiment sudden return promotes mixing by abrupt equilibration.

In a further embodiment it is possible to include a needle shield in theinjection device. This shield would cover the needle and retract as theuser pushes the device against their skin for injection. Once the needleis removed from the skin, the shield would move back into place andthereby activate a locking mechanism so that the user is unable toretract the needle shield again.

In yet another embodiment the device comprises a unit and a primarypackaging,

wherein the unit comprises the first chamber within its housing,

wherein the primary packaging comprises the second chamber, the firstpiston and the second piston, wherein the primary packaging isattachable to the distal end of the unit,

wherein a needle is attachable to the distal end of the unit or thesecond piston,

wherein the fluid communication path between the first chamber and thesecond chamber is provided either by penetration of the needle attachedto the distal end of the unit through a septum seal provided within orat the second piston or by penetration of the needle attached to thesecond piston through a membrane covering the first chamber of the unit.

The primary packaging may be attached to the distal end of the unit by aluer lock or by welding, wherein in both cases detachment of the deviceand the primary packaging prior injection is possible. Alternatively,another releasable attachment of the primary packaging to the unit maybe used.

In one embodiment in an initial position after attachment of the primarypackage to the distal end of the unit by the luer-lock the needlepierces the second piston to a certain extend but does not penetrate aseptum seal within the body of the second piston.

In another embodiment the primary packaging comprises two partsattachable to each other, a first part comprising the second chamberwith the first and second piston and the second drug component, and asecond part comprising the activation mechanism.

The primary packaging may comprise an activation mechanism foractivating the device, wherein the activation mechanism is adapted suchthat a user operation of the activation mechanism causes a release oroperation of a driving mechanism which applies an axial force into oneaxial direction onto the first piston, for example, leading to apressure increase within the second chamber and respective movement ofthe second piston into the same axial direction. In one embodiment thedriving mechanism comprises an initially compressed spring held in placeby a clip element, and user operation causes the release of the clipelement. Alternatively, the driving mechanism comprises a gas springheld in place by a clip element, and user operation causes the releaseof the clip element. In another embodiment the driving mechanismcomprises a linear electromechanical actuator. In particular, a costeffective embodiment comprises the possibility that the drivingmechanism is released by means of a clip mechanism.

According to one aspect the activation mechanism may comprise a capwhich covers the driving mechanism, wherein the cap is adapted such thatby pushing in an axial direction the driving mechanism is released oroperated. Alternatively, the whole primary package may be moved withrespect to the unit, for example during attachment of the primarypackage to the unit.

The user convenience of the embodiment of the device comprising theprimary packaging and the unit is extremely good because the user hasonly to press a button on the distal end of the primary packaging andwait until mixing and/or reconstitution is complete. This may bevisually checked by the user. Then, the user may remove the unit fromthe primary packaging, may expel air by priming, if necessary, as usualand injects the drug. There is no danger of contamination during themixing and/or reconstitution process as it all occurs within afactory-sealed environment. The mixing is very predictable andconsistent and the user has only two disposable parts, namely theprimary packaging and the unit. The user does not have to ensuresterility for any part as this is maintained throughout use.

In another embodiment the needle is attached to the distal end of theunit, wherein the second piston comprises a recess in which the distalend of the needle is located at the end of movement of the secondpiston.

According to another aspect the second material is driven into the firstchamber by a high speed jet. The high speed jet has a fluid velocity of2.5 m/s to 25 m/s, preferably a fluid velocity above 5 m/s. This highspeed jet is produced in one embodiment by the second piston and/or theinner surface of the first chamber, wherein at least one of the secondpiston and the inner surface of the first chamber within the inletregion is structured in a way that turbulences occur in the fluid andenhance the mixing process. For example the second piston and/or theinner surface of the first chamber comprise a certain profile in orderto enhance the mixing property of the high speed jet, e.g. concavecavities or one or more vanes at the front end of a plunger defining oneend of the first chamber.

The above problem is further solved by a mixing and/or reconstitutionmethod using a device, wherein the device comprises a housing, a firstchamber within the housing, wherein the first chamber contains a firstmaterial, a second chamber comprising a first piston and a secondpiston, and a second fluid material initially contained within thesecond chamber between the first piston and the second piston,comprising the following steps after activation of the device:

-   -   moving of one of the first piston and the second piston in an        axial direction of the device,    -   moving of the other one of the first piston and the second        piston into the same axial direction of the device,    -   opening a fluid communication path between the second chamber        and the first chamber and    -   expelling the second material into the first chamber where the        second material mixes and/or reconstitutes with the first        material.

In one embodiment the other one of the first piston and the secondpiston comprises a needle which pierces a seal or membrane when movedinto the axial direction in order to open the fluid communication pathbetween the second chamber and the first chamber.

Activation is facilitated, for example, by axially moving a plunger,e.g. into proximal direction, within the housing of the device, whereinthe plunger closes a proximal end of the first chamber within thehousing and contains the second chamber.

In another embodiment the axial movement of the second piston forces aplug connected with the second piston to move through a through holewithin the distal end of the plunger thereby creating the fluidcommunication path between the second chamber and the first chamber.

According to another aspect the device comprises a unit and a primarypackaging, wherein the unit comprises the first chamber and the primarypackaging comprises the second chamber with the first piston and thesecond piston, wherein prior activation the primary packaging isattached to the distal end of the unit and a needle is attached to theprimary packaging or the unit for opening of the fluid communicationpath between the first chamber and the second chamber.

In one embodiment, after activation the fluid communication path betweenthe first chamber and the second chamber is opened either by penetrationof the needle attached to the distal end of the unit through a septumseal provided within or at the second piston or by penetration of theneedle attached to the second piston through a membrane covering thefirst chamber of the unit.

BRIEF DESCRIPTION OF THE FIGURES

Certain embodiments will now be described in further detail withreference to the accompanying schematic drawings, wherein

FIG. 1 shows a concept sketch of a first embodiment of an injectiondevice in a sectional view,

FIG. 2 shows the first embodiment of an injection device in a sectionalview prior activation,

FIG. 3 shows the device of FIG. 2 after activation,

FIG. 4 shows the device of FIG. 2 during reconstitution,

FIG. 5 shows the device of FIG. 2 at the beginning of injection,

FIG. 6 shows the device of FIG. 2 after injection,

FIG. 7 shows a detail of the device of FIG. 2 in a sectional view,

FIG. 8 shows a detail of the plunger of the device of FIG. 2,

FIG. 9 shows a concept sketch of another embodiment of an injectiondevice with a primary package in a sectional view,

FIG. 10 shows another embodiment of an injection device with a primarypackage in a sectional view,

FIG. 11 shows the embodiment of FIG. 10 during a first step of amixing/reconstitution process in a sectional view,

FIG. 12 shows the embodiment of FIG. 10 during a second step of amixing/reconstitution process in a sectional view,

FIG. 13 shows the embodiment of FIG. 10 during a third step of amixing/reconstitution process in a sectional view,

FIG. 14 shows the embodiment of FIG. 10 during a forth step of amixing/reconstitution process in a sectional view,

FIG. 15 shows the syringe of the embodiment of FIG. 10 prior injectionin a sectional view,

FIG. 16 shows an injection device and a detail of a mixing unit of anembodiment of a system in a sectional view as a concept sketch,

FIG. 17 shows an injection device received by a mixing unit of anotherembodiment of a system in a perspective and sectional view prioractivation of the mixing and/or reconstitution step,

FIG. 18 shows the system of FIG. 17 prior to insertion of the injectiondevice into the mixing unit in a sectional view,

FIG. 19 shows the system of FIG. 17 after insertion of the injectiondevice into the mixing unit in a sectional view,

FIG. 20 shows the system of FIG. 17 after activation of the mixingand/or reconstitution step and the initial electromagnetic fieldproduced by the electromagnetic unit in a sectional view,

FIG. 21 shows the system of FIG. 17 during the mixing and/orreconstitution in a sectional view,

FIG. 22 shows the system of FIG. 17 after the mixing and/orreconstitution step and during withdrawal of the injection device fromthe mixing unit in a sectional view,

FIG. 23 shows the injection device of the system of FIG. 17 during drugadministration,

FIG. 24 shows a slug-like element of the system of FIG. 17 in aperspective view,

FIG. 25 shows a distal section of a plunger of another embodiment of aninjection device in a perspective and sectional view,

FIG. 26 shows a first set of force profiles for different active coilsets of the electromagnetic unit of the mixing unit of FIG. 17 in adiagram in which the electromagnetic force on the slug-like element isshown as a function of the axial position within the opening,

FIG. 27 shows a second set of force profiles for different active coilsets of the electromagnetic unit of the mixing unit of FIG. 17 in adiagram in which the electromagnetic force on the slug-like element isshown as a function of the axial position within the opening,

FIG. 28 shows a third set of force profiles for different active coilsets of the electromagnetic unit of the mixing unit of FIG. 17 in adiagram in which the electromagnetic force on the slug-like element isshown as a function of the axial position within the opening,

FIG. 29 shows an injection device and a detail of a base station ofanother embodiment of a system in a longitudinal section as a conceptsketch,

FIG. 30 shows another embodiment of a system comprising an assembly withan injection device, a vial and a supporting unit as well as a basestation in a perspective view from the side, wherein the base station isshown partially transparent,

FIG. 31 shows the disposable subassembly from FIG. 30 in an explodedview from the side,

FIG. 32 shows the assembly of FIG. 31 prior fixing at the base stationin a longitudinal section,

FIG. 33 shows another embodiment of a system comprising an assembly withan injection device, a vial and a supporting unit as well as a basestation in a perspective view from the side, wherein the base station isshown partially transparent,

FIG. 34 shows the disposable subassembly from FIG. 33 in an explodedview from the side,

FIG. 35 shows the subassembly of FIG. 34 in a longitudinal section priorreconstitution,

FIG. 36 shows the subassembly of FIG. 34 in a longitudinal section afterreconstitution, and

FIG. 37 shows the base station of FIG. 33 in a perspective view from theside, partially transparent.

DETAILED DESCRIPTION

The first embodiment of an injection device in form of a syringe 100depicted in FIGS. 2 to 8 comprises a housing 101 and a needle 102attached at its distal end. The principle of operation is demonstratedby FIG. 1. The needle 102 is in fluid communication with a first chamber105 accommodated within the housing 101, wherein the first chamber 105contains a first drug component, for example a lyophilized drug.

A plunger 107 is movable within the housing 101 in an axial(longitudinal) direction with regard to the syringe 100 or housing 101,wherein the plunger 107 closes the first chamber 105 at its proximalend.

Within the plunger 107 a second chamber 109 is provided containing asecond drug component, for example a diluent. The second chamber 109 isclosed at its distal end by a lower piston 111 and at its proximal endby an upper piston 112. The lower piston 111 and the upper piston 112are movable within the plunger 107. The plunger 107 is formed as asleeve-like element, wherein the hermetic seal of the first chamber atthe proximal end of the first chamber 105 is provided by a distal endsection 108 which has a bigger diameter than the remaining section ofthe plunger (except a handle 113). The diameter of the distal endsection 108 corresponds to the inner diameter of the first chamber 105.The proximal end of the plunger 107 is formed as the handle 113. Thedistal end section of the plunger 107 comprises a, for examplecylindrical through hole 114. As well as admitting the passage of fluid,this through hole 114 acts as a guide for a stud-like cotter pin 117,ensuring that piston 111 moves in a stable axial fashion.

The needle 102 is covered at its distal end by a needle boot 115. Theneedle boot 115 is required to prevent pressure differences fromallowing air into the syringe 100.

In the initial position the lower piston 111 forming a seal between thefirst chamber 105 and the second chamber 109 while it is sitting in thearea of an even inner surface of plunger 107. To activate mixing and/orreconstitution process of the syringe 100 shown in an initial state inFIG. 2, in a proximal stroke, a user pulls back on the plunger 107 outof the syringe 100 into a proximal direction using the handle 113 (seein FIG. 3 the fully pulled back position of plunger 107). This causes aregion of low pressure to form inside the syringe 100, in particular thefirst chamber 105. The pressure further decreases as the plunger 107 isfurther pulled back. The plunger 107 is prevented from moving back toits original position shown in FIG. 2 by a ratchet system betweenplunger 107 and housing 101 (see FIG. 8). An outer projection fromplunger 107 runs inside a track in housing 101. This projection issprung to engage with a ratchet 101 a in the track, so that plunger 107can only move in one direction, until it has completed the full extentof its travel: then, the protrusion is guided into a smooth return track101 b. The ratchet system with ratchet 101 a ensures that the plunger107 is pulled far enough out of the syringe 100 before it begins to moveback into the syringe 100 along return track 101 b, thereby guaranteeingthat a minimum level of suction is generated (see FIG. 3). The suctionprovided by the low pressure is needed to pull the first drug componentthrough the through hole 114 within the plunger 107 and also to promotemixing of the first drug component and the second drug component withinthe first chamber 105.

The pressure difference between the inside of syringe, in particularinside the first chamber 105 and the second chamber 109, and atmospherecreates a force on the lower piston 111. This force is transferredthrough the second drug component contained in the second chamber 109and onto the upper piston 112. They are thereby caused to move theplunger 107 down. The cotter pin 117 thereby moves through the throughhole 114 and the lower piston 111 until the upper piston 112 hits thelower piston 111 (see FIG. 3). The cotter pin 117 and/or the lowerpiston 111 comprise a compressible outer surface which interacts with aset of longitudinal ribs 120 (web-like elements) provided at the distalend of the inner surface of the plunger 107 forming an uneven innersurface (see FIG. 7). When the lower piston 111 is pushed into theuneven area (ribs) the seal is broken. These ribs 120 force gaps to openup around the lower piston 111 and fluid can go through and thereforeopen a fluid communication path between the second drug componentcontained in the second chamber 109 and the first drug componentcontained in the first chamber 105 via the through hole 114. The seconddrug component flows out the distal end of the plunger 107 and into thefirst chamber 105 of the syringe 100 (see FIG. 4, it shows the positionin which the second drug component has completely emptied into the firstchamber 105). All of the second drug component will have passed into thefirst chamber 105 of the syringe 100 before the plunger 107 is pulledback completely. As plunger 107 moves back further, pressure in chamber105 drops to near vacuum.

Once the plunger 107 has completed its stroke in the proximal direction,the ratchet mechanism will permit it to move back into the syringe 100until pressure has equilibrated within the syringe 100 and atmosphere.This return is sudden, and the abrupt equilibration promotes mixingbetween the first and the second drug component in chamber 105.

At this point visual check of mix clarity is needed before the mixedand/or reconstituted drug comprising the first drug component and thesecond drug component can be injected. If it has not been fully mixed,the user must manually shake the device to fully mix the drug. Once thedrug is fully mixed, it can be injected using the plunger 107 by movingit into distal direction by means of handle 113 as with any standardsyringe (see FIG. 6 showing the syringe 100 post injection).

When plunger 107 is moved to inject drug, the pressure increase withinthe syringe 100 causes the upper and lower pistons 111, 112 to move intoproximal direction until a snap or clip member 112 a at the proximal endof the upper piston 112 and snap or clip member 107 a at the innersurface of the plunger 107 interact and mechanically lock (see FIG. 5,realized for example by a hook and a protrusion). This prevents anyincrease of pressure inside the syringe 100 from forcing the lowerpiston 111 and the upper piston 112 further back into the plunger 107and therefore the second drug or the mixture of first and second drugcannot move back into the plunger 107. In this position the lower piston111 does not interact with the ribs 120 of the plunger anymore and hencethe lower piston 11 closes the second chamber 109. Note that dependingon various detail design features, this may have already occurred duringthe sudden equilibration of pressure described above.

In an alternative embodiment, at the point where the user visuallychecks the clarity of the mix comprising the first and the second drugcomponent, instead of manually shaking the syringe 100 it is allowedthat the plunger 107 is continuously pulled back in order to create aregion of low pressure in 105 again. This cyclical process is allowed bythe ratchet mechanism forming a closed loop, which the mechanism of 107can go around repeatably. The user may pull back the plunger and releaseit as many times as they like until the first and second drug componentsare fully mixed.

In a further embodiment the injection device is an autoinjector. Thisautoinjector may be constructed such that it includes an automatedmovement of the plunger in the reverse direction so that mixing of thefirst and second drug component is performed without user intervention.An optical check of clarity of the mix comprising the first and seconddrug component is still required from the user so that the autoinjectorwould need to be able to continue the mixing cycle for as long as theuser deems necessary. This may be realized using the repeated creationof low pressure regions as outlined above.

The above mentioned communication between the first and the secondchamber 105, 109 is provided by breaking of the seal provided by thelower piston 111 within housing 107, as the lower piston 111 interactswith the ribs 120 of the plunger 107. Alternatively, a bypass pathwaymay be created which allows the second drug component to flow around thepiston 111. As a further alternative there may also be used some form ofneedle/septum interaction as depicted in FIG. 1, where a needle 122attached to the distal end of the lower piston 111 pierces a membrane125 of the distal end section 108 of the plunger 107.

The needle 102 may be changeable and removably attachable to theinjection device.

In a further embodiment rather than the ratchet mechanism being insidethe injection device 100, it could be housed outside of the injectiondevice within a separate housing. The housing would hold syringe 100 andplunger 107, and guide their relative motion in the same way that theratchet achieved. This will save space in the disposable device, as itremoves a complex interaction between parts 100 and 107.

In a further embodiment a combined axial and rotational (twisting)motion could be conducted by the user to pull back the plunger 107,similar to those systems found in standard pen injectors, instead of theaxial movement described above.

In a further embodiment it is possible to include a needle shield in theinjection device. This shield would cover the needle 102 and retract asthe user pushes the device against their skin for injection. Once theneedle 102 is removed from the skin, the shield would move back intoplace and thereby activate a locking mechanism so that the user isunable to retract the needle shield again.

The above mentioned embodiments explained with reference to FIGS. 1 to 8have the advantage that they provide an improved user operabilitybecause the user needs only to pull back the plunger until it naturallysnaps back into the injection device. Further, the ratchet mechanismregulates the process so that the result is independent of user skill.Further, the user may perform a visual check of clarity of the mix ofthe first and second drug components. The user only needs to gentlyshake the injection device to ensure complete mixing of any residualfirst or second drug component. Additionally, during the reconstitutionprocess air is not introduced. The injection is analogue to the standardprocedure which the patient knows. Further, there is no danger ofcontamination during the mixing and/or reconstitution process as it alloccurs within a factory-sealed environment. The mixing of the first andsecond drug components is very predictable and consistent. Additionally,the user has only one disposable part and does not have to ensuresterility for any part as this is maintained throughout use. Althoughthere is use of a low pressure region to promote mixing of the first andsecond drug components, this low pressure does not have to be heldduring device storage.

The embodiment shown in FIGS. 10 to 15 and as a concept sketch in FIG. 9comprises a syringe 500 with a housing 501 and a needle 502 attached tothe distal end of the syringe 500. The needle 502 is in fluidcommunication with a first chamber 505 accommodated within the housing501 of the syringe 500. The first chamber 505 is defined at its proximalend by a plunger 507. The first chamber 505 comprises a first drugcomponent, for example a lyophilized drug. The needle 502 is suitablefor injection of a drug into a patient. A minimal volume of air is heldwith the first drug component within the first chamber 505.

Additionally, a primary package 510 is provided comprising a housing 510a (custom housing). The primary package 510 contains within a secondchamber 509 formed by its housing 510 a a second drug component, forexample a diluent, accommodated between a lower piston 511 and an upperpiston 512. The lower piston 511 and the upper piston 512 are bothmoveable within the housing 510 a of the primary package in an axialdirection, wherein the lower piston 511 is accommodated more proximalthan the upper piston 512. The lower piston 511 contains a septum sealwithin its body. Additionally, it comprises at its upper or distalsurface a recess or indentation 511 a. The upper piston 512 is incontact on its distal side with a compression spring 530 as a drivingmechanism which is initially compressed and held in place by a clipmechanism 536. A cap 535 on the distal end of the primary package 510sits over the clip mechanism 536, i.e. the cap covers the clip mechanism536 with the spring 530. When the cap 525 is pushed downwards, e.g. intoproximal direction, it will release the clip mechanism 536 and allow thespring 530 to apply an axial force into proximal direction to the upperpiston 512. At the proximal end of the primary package 510 attachmentmeans, for example one part of a luer-lock 537, is provided. As shown inFIG. 10 prior to activation of the mixing and/or reconstruction processthe primary package 510 is attached to the distal end of the syringe 500by the attachment means, for example the luer-lock 537. This luer-lock537 provides a seal to ensure that the exposed parts of the needle 502remain sterile until injection, e.g. the space around the needle 502 issealed during device assembly and remains so until immediately prior toinjection. Further, an O-ring 538 is provided which contacts the housing510 a of the primary package 510 and the luer-lock 537 forming anadditional seal.

A different attachment means between the syringe 500 and the primarypackage 510 can be used, rather than luer-lock. Any attachment mechanismmust remain secure over a shelf-life of one year and additionally beeasy to engage and disengage by hand.

In an initial position shown in FIG. 10 after attachment of the primarypackage 510 to the distal end of the syringe 500 by the luer-lock 537the needle pierces the lower piston 511 to a certain extend but does notpenetrate the septum seal within the body of the lower piston 511.

In order to start with the mixing and/or reconstitution process the userpresses on the cap 535 and moves it into proximal direction (see arrow540 in FIG. 11). Thereby, the clip mechanism 536 retaining thecompression spring 530 is disengaged and allows the compression spring530 to extend (see FIGS. 11 and 12). The disengagement may work in oneembodiment as follows. The upper piston 512 may comprise one flexibleclip or more than one flexible clips (not shown) which pass through ahole in the housing 510 a, and act against an upper face of housing 510a. The cap 535 comprises a recess (not shown) at its front end over therespective flexible clip. As cap 535 is pressed down, the clip entersthe respective recess. Each recess is chamfered so that as the clipsenter, they are compressed together, disengaging them from housing 510aallowing the spring 530 to extend in axial direction. Both, the forcefrom the extending spring 530 and from the user's hand can contribute topush the subsystem comprising the second drug component (the second drugcomponent plus the upper and the lower piston 511, 512) along an axialproximal direction of the primary package 510. Thereby the needle 502 isforced to penetrate the septum seal of the lower piston 511 therebyforming a fluid communication between the second chamber 509 and thefirst chamber 505 of the syringe 500. The lower piston 511 is stoppedfrom moving further by an end-stop feature within the primary package510, for example a projection 513 at the inner surface of the housing510 a (see FIG. 10). In this position the distal end of the needle 502is located within the recess 511 a of the lower piston 511. The upperpiston 512 is further forced to move into proximal direction and intothe direction of the lower piston 511 thereby increasing the pressurewithin the second chamber 509 and pushing the second drug componentthrough the needle 502 into the first chamber 505 (see arrow 541 in FIG.12).

The recess 511 a at the lower piston 511 allows the needle 502 toprotrude through the lower piston without ever touching the upper piston512 (see FIGS. 11 and 13). It is noted that the lower piston 511 and theupper piston 512 eventually met when whole content of the second drugcomponent is transferred from the second chamber 509 into the firstchamber 505. The recess 511 a has the advantage that if the upper piston512 contacts the lower piston 511 the needle 502 would not contact theupper piston 512 and consequently the flow of the second drug componentthrough the needle 502 would not stop. In another embodiment the recessmay be located in upper piston 512 rather than in lower piston 511, forthe same effect.

When the second drug component enters the first chamber 505 it will beunder substantial pressure which creates a high speed jet (for examplewith a fluid velocity of 2.5 m/s and faster, preferably with a velocityof 5 m/s and faster) in the case that the second drug component isfluid. This jet dislodges the first drug component and causes turbulentmixing. All of the second drug component will be mixed into the firstdrug component by the time the upper piston 512 finishes expelling ofthe second drug component into the first chamber 505. The spring 530generates all of this pressure to drive the second drug component andensures reliable and repeatable mixing independent of user strength orskill. The user may visually check that the first and second drugcomponents are fully mixed.

Then the user may unscrew (see arrow 542 in FIG. 14) or otherwise detachthe primary package 510 from the syringe 500. The syringe is now readyto inject (see FIG. 15) the mixed and/or reconstituted drug containedwithin the first chamber 505.

In another embodiment rather than using a standard syringe 500 for theaccommodation of the first drug component, a cartridge could be used tobe placed in another device for injection.

In one embodiment the plunger 507 within the syringe 500 may be customshaped to improve the mixing resulting from the fluid jet. For example,the plunger 507 may comprise one or more concave cavities at its frontend defining the first chamber 505. Within such cavity the jet of fluidis deflected out to better penetrate the corners of first chamber 505.Alternatively or additionally, one or more vanes at the front end ofplunger 507 defining the first chamber 505 may achieve a similar effect.

In another embodiment the proximal end of the needle 502 within thesyringe 500 may be shaped so that a jet of fluid is directed towards theproximal direction, keeping the majority of turbulent mixing close tothe first drug component. For example, the proximal end of needle 502may have a bend so that the jet enters first chamber 505 at an obliqueangle, setting up swirl flows to promote mixing. Alternatively oradditionally, through holes within the side wall of the proximal end ofthe needle 502 may be provided in order to create multiple jets.

In a further embodiment the primary package 510 may be housed inside anautoinjector so that manual injection is not necessary. The autoinjectorwould have to allow removal or separation of the primary package 510prior to insertion.

In another embodiment the attachment of the syringe 500 and the primarypackage 510 may be more permanent. For example the syringe 500 and theprimary package 510 may be welded together, with the weld creating ahermetic seal that replaces the function of the seal 538 and theluer-lock connector 537. In this case, a mechanism must allow thesyringe 500 and the primary package 510 to separate before injection.This may be realized by a snap mechanism, wherein the housing 501 of thesyringe 500 and the housing 510 a of the primary package 510 may simplysnap apart under user pressure.

In a further embodiment, the primary package 510 may comprise twoseparate parts, one holds the spring and the other one holds just thesecond chamber with the second drug component and the upper and lowerpiston 511, 512. This would remove the need to weld the primary package510 together during manufacture. The parts would have to interlock priorattachment to the syringe 500.

In further alternative embodiments, the force for driving the upperpiston 512 may be generated not by a compressed spring 530 as explainedabove but instead by another driving mechanism, for example by a gasspring or by a linear electromechanical actuator.

In another embodiment the sizes of the first chamber 505 and the secondchamber 509 as well as the needle gauge can be customized in order tocreate a suitable jet profile for effective mixing of the particularfirst and second drug components.

The needle 502 could, instead of being staked into the syringe 500, bechangeable. In this case one needle may be used for mixing and/orreconstitution but the user swaps it for a separate, sterile needle forinjection.

In a further embodiment the mixing and/or reconstitution process may beactivated by movement of the primary package, for example its housing,rather than a pushing onto the cap 535. For example, when the userattaches the primary package 510 to the syringe 500 the lower and upperpistons 511 are automatically driven such that the needle 502 fullypenetrates the septum, starting the flow of the second drug componentinto the first chamber 505.

The advantage of the embodiment explained above with regard to FIGS. 9to 15 consists therein that the user convenience is extremely goodbecause the user has only to press a button on the distal end of thedevice and wait until mixing and/or reconstitution is complete. This maybe visually checked by the user. Then, the user may unscrew the syringe500 from the primary package 510, expels air by priming as usual andinjects the drug. There is no danger of contamination during the mixingand/or reconstitution process as it all occurs within a factory-sealedenvironment. The mixing is very predictable and consistent and the userhas only two disposable parts, namely the primary package 510 and thesyringe 500. The user does not have to ensure sterility for any part asthis is maintained throughout use.

The embodiment described in FIGS. 17 to 28 comprises an injection devicein form of a syringe 200 and a mixing unit in form of a base station250. The syringe 200 comprises a housing 201 with a first chamber 205and a plunger 207 which closes the first chamber 205 at its proximalend. At its distal end the plunger 207 forms a second chamber 209 withina respective inner space of the plunger 207. The first chamber 205contains a first drug component, for example a diluent, wherein thesecond chamber 209 contains a second drug component, for example alyophilized drug. Additionally, a moveable slug-like element 210 with amagnetic or paramagnetic characteristic is provided within the secondchamber 209. The distal end of the second chamber 209 of the plunger 207is covered by a seal 211. The seal may be realized by a foil ormembrane, for example comprising or consisting of an aluminium-polymerlaminate or a low-permeability polymer such as a cyclic olefin. At thedistal end of the housing 201 of the syringe 200 a needle 202 with aneedle cover 215 is attached. The needle 202 is in fluid communicationwith the first chamber 205 of the syringe 200. The needle cover 215protects the needle 202, avoids its contamination and prevents the userfrom needle sticks.

The slug-like element 210 may comprise or is composed of, for example,at least one of the following materials comprising sinteredNeodymium-Iron-Boron (NdFeB), preferably with a medical-grade coating,Samarium-Cobalt (SmCo) and Aluminium-Nickel-Cobalt (AlNiCo). The middleor main section of the element 210 is preferably formed as a cylinder.Alternatively, it may have a shape of a barrel or of a section of asphere. One distal end 210 a of this element 210, which is shown in FIG.24 in detail, may be shaped as a sharp tip to puncture the seal 211.Additionally, the proximal end 210 b of the element 210 may be taperedin order to help the element 210 to slide back up into the plunger 207,so that it does not get trapped between the plunger 207 and the innerwall of the syringe housing 201, thereby preventing full injection ofthe mixed and/or reconstituted drug.

The seal 211 may be provided such that it bursts in a way that does notcreate loose parts. Equally, the proximal end of the needle 202 may bemade too small for foil parts to enter, or a filter may be added insidethe syringe (e.g. at the distal end of the first chamber, within thefirst chamber 205) preventing that foil parts enter the needle 202.

The base station 250 comprises a series of electromagnetic coils 260 aplus milled steel pole pieces 260 b accommodated in between two adjacentelectromagnetic coils 260 a to guide the magnetic flux and improveefficiency. The electromagnetic coils 260 a and steel pole pieces 260 btogether form the electromagnetic unit 260. The electromagnetic unit 260encases a cylindrical opening 265 which is provided to receive thedistal end of the syringe 200. An inserted syringe 200 within theopening 265 is shown for example in FIGS. 17, 19, 20, and 21. The basestation 250 further comprises a control unit 270 and a power supply withbatteries 273 in order to provide electrical energy for the componentsof the base station 250. Further, a button 275 is provided by pressingof which the mixing and/or reconstitution of the first and second drugcomponent may be activated by the user when the syringe 200 is insertedin the opening 265. The opening of the base station 250 may contain asensor for the syringe 200 recognizing the correct and full insertion ofthe syringe 200 within the opening 265. In case the sensor does notnotice a syringe 200 correctly inserted within the opening 265 anactivation of the button 275 shall not start the mixing and/orreconstitution step.

In the first step, the syringe 200 is inserted into the opening 265 ofthe base station 250 (see FIG. 18) so far that its body 201 is fullyreceived by the opening 265 (see arrow 213). By pushing the button 275the user activates the electromagnetic unit 260 energizing the coils 260a so that a large force into an axial direction of the syringe 200, forexample a distal direction, is exerted on the slug-like element 210during a pre-determined time period, causing it to puncture the seal211. Thereby it is allowed to the first and second drug component to mixwithin the first chamber 205, for example to reconstitute bothcomponents.

In one embodiment the base station 250 comprises a separate interlocksystem holding the syringe 200 within the opening 265 of the basestation 250 until mixing is complete.

Once the element 210 has punctured the seal 211 it is free to move alongthe entire length of the first chamber 205 into an axial direction ofthe syringe 200 back and forth (see arrow 214). FIG. 20 shows lines ofmagnetic flux with flux density, for the initial stage, in which theslug-like element 210 is accelerated in order to pierce the seal 211.The lines of the magnetic field are marked with the reference number262. Afterwards, the coils 260 a and the magnetic element 210 form abrushless linear motor, i.e. a Lorentz force device, whereby energizingdifferent coils in different directions and at different times causesthe element 210 to move backwards and forwards in the axial(longitudinal) direction (arrow 214) of the syringe 200 within apre-determined time period to effect mixing within the first chamber 205(see FIG. 21). In one embodiment the base station 250 comprises fourcoils 260 a accommodated side by side along the axial direction (seearrow 214), wherein at any one time, two coils 260 a are active (seeFIG. 20) alternating with the other two coils 260 a. The two activecoils 260 a are energized in opposite directions, and interact with thetwo magnetic poles of the element 210 to generate an axial force suchthat, in one step, one coil 260 a repels one magnetic pole of theelement 210 and the other coil 260 of the two active coils attracts theother magnetic pole of the element 210. Only energizing coils 260 aclose to element 210 improves the efficiency of the system. By settingprecise levels of power in each coil 260 a, the speed and position ofthe element may be accurately controlled. If each coil 260 a has aresistance of 40 Ohms, the drive system may include a boost powersupply, e.g. providing 200 V, driving the coils 260 a via a half bridgefor 0.1 seconds. This could generate 1 kW in the coils, which wouldgenerate the large forces needed to initially puncture the foil seal.The control unit 270 of the base station 200 provides a predefinednumber of cycles of energizing different coils of the electromagneticunit 260 that guarantees a homogenous reconstituted or mixed drug. Atthe end of the process (see FIG. 22), the element 210 rests in aposition within the previous second chamber 209 of the plunger 207whereby it does not hinder injection. As shown in FIG. 24, the element210 has a tapered proximal end 210 b to help it re-enter the plunger207. By means of the control unit 270 which is connected with theelectromagnetic unit 260 a smooth slide of the element 210 into theplunger 207 is provided during injection.

Finally, as shown in FIG. 22, the syringe 200 is removed from the basestation 250. In order to inject the mixed and/or reconstituted drugcontaining the first and the second drug component the user removes theneedle cover 215, expels any air from the syringe by means of primingand finally injects the drug mixture (see FIG. 23).

The FIGS. 26 and 27 show the forces generated at 10 W and 900 W for fivedifferent coils of the electromagnetic unit 260, respectively, for thegeometry shown in FIG. 17. At 10 W, forces are ample to dislodge thesecond drug component and mix the first and second drug componentreliably. At 900 W, forces are adequate that the element 210 isaccelerated and punctures the seal 211, subject to the geometry of theslug-like element 210. This high power is only needed for a very briefperiod of time, namely the time in which the seal 211 is punctured, sototal energy used is low and the coils of the electromagnetic unit 260do not overheat.

In another embodiment an additional plate-like metal element 220, madefrom a soft magnetic material for example comprising steel, could beused to hold the paramagnetic or magnetic element 210 in place until thesyringe 200 is placed in the base station 250 and activated, and also tokeep the element 210 inside the plunger during injection. The plate-likeelement 220 is accommodated within the plunger 207 close to the proximalend of the second chamber 209 (see FIG. 25). The plate-like element 220is as close as possible to element 210, by making the wall between itand chamber 209 as thin as practical, preferably the thickness may beless than 1 mm. This means that element 220 can be small and stillprovide sufficient attraction to element 210. For example, element 220may have a thickness of more than 0.5 mm, preferably more than 1 mm. Theplate-like element 220 prevents that no amount of inadvertent agitationduring (e.g.) shipping or dropping the device prior to use will causethe seal 211 to rupture. In an alternative embodiment the element 220could be a separate element which the user has to remove or an elementthat is dislodged on insertion of the syringe 200 in the base station250. For example, the element may be a steel collar piece accommodatedaround the outside of housing 201 of the syringe 200, which is slid awayon insertion into base station 250. Anyhow, the element 220 generates asmall enough force that the coils of the electromagnetic unit 260 caneasily overcome it.

If the slug-like element 210 is a permanent magnet, it is preferred touse a medical-grade coating to prevent contact between the magneticmaterial and the first or second drug component.

Instead of using a moving magnetic material for the electromagneticelement 210 (a “Lorentz force” device or linear brushless motor), theelement 210 could made of a soft magnetic material, e.g. mild steel. Inthis case only one coil is needed to be activated at any time and thesyringe works as a simple electromagnetic, e.g. a solenoid actuator.FIG. 28 shows that such an actuator generates even higher instantaneousforces for a given power input but these forces vary more with theposition of the soft magnetic element within the first chamber 205 sothat the coils must be carefully sized/placed to avoid positions of theelement 210 in which no force is generated. If the element 210 is a softmagnetic material, it could be, for example, medical-grade stainlesssteel, in which case no coating is required. In that case, the magneticelement 210 may form sharp edges to more effectively puncture the foil.

In another embodiment instead of using a simple syringe, the injectiondevice can be complete autoinjector. The above explained process may beconducted as indicated above: the autoinjector containing the first andsecond chambers comprising the first and second drug component isinserted into the base station, the components are mixed and theautoinjector is removed ready to use.

As a further embodiment, e.g. for high-value drugs, it may beeconomically viable to include the electromagnetic unit, the powersupply and the control unit into a disposable component of the injectiondevice so that no separate base station is needed.

In a further embodiment the internal shape of the needle 202, of thefirst chamber 205 and of the housing 201 of the syringe 200 may bedesigned such that the element 210 will not hinder injection should theelement 210 remain in the first chamber 205 after mixing.

Rather than a syringe or an autoinjector, the injection device may be acartridge suitable for use with a separate injection device. In otherwords, it is a syringe, but missing the long plunger that enables a userto carry out injection, and also missing the needle: the injectiondevice includes the system for penetrating the skin, and also the systemfor driving injection.

The system shown in FIGS. 16 to 28 comprising a syringe 200 and a basestation 250 for drug reconstitution and/or mixing is extremely goodoperationally because there is no danger of contamination during thereconstitution process as it all occurs within a factory-sealedenvironment. The disposable part comprising the syringe 200 is verycompact. The mixing/reconstitution is very predictable and consistentwith a low amount of steps. There is only one disposable part perinjection. The design of this base station offers maximum flexibilityacross injection device types namely pre-filled syringes, autoinjectorsand cartridges. The injection device does not need a needle fitted inadvance of reconstitution.

The embodiment of a drug reconstitution system shown in FIGS. 29 to 32comprises a prefilled injection device in form of a syringe 300 with ahousing 301 and a vial 308. The syringe 300 comprises a first chamber305 which contains a first fluid drug component, for example a diluent.The vial 308 comprises a second chamber 309 containing a second solidand/or fluid drug component, for example a lyophilized drug.Additionally, the system comprises a supporting unit 310 which consistsof, for example, two parts 310 a and 310 b (see FIG. 31) which may bereleasable connected to each other, e.g., by means of a snap connection.The syringe 300 is further connected to a needle 302, wherein the needle302 is covered by a needle boot 315. The syringe 300 further comprises aplunger 307 at its proximal end opposite from the distal end of thesyringe 300 which is connected to the needle 302. The plunger 307 ismovable within the housing 301 of the syringe 300 along an axial(longitudinal) direction of the syringe 300. The plunger 307 closes theproximal end of the first chamber 305. If the plunger 307 is moved inproximal direction an underpressure is generated within the firstchamber 305. If the plunger 307 is moved in distal direction the firstdrug component is expelled from the first chamber 305 through the needle302.

The drug reconstitution system further comprises a base station 350comprising a housing 351 and, within the housing 351, at least one driveunit 370.

The supporting unit 310 is formed like a capsule or a hollow cylinderwhich comprises two sections with different diameter when both parts 310a, 310 b shown in FIG. 31 are connected to each other (see FIG. 30).Alternatively, the connection of both parts 310 a, 310 b of thesupporting unit 310 may be a hinge connection. The supporting unit 310forms a first recess 311 and the second recess 312 on the inner side ofeach part 310 a, 310 b such that the supporting unit 310 locks thepre-filled syringe 300 and the vial 308 in a locked position duringtransit and storage, preventing them from making contact with eachother. Therefore, the syringe 300 is fixed such in the first recess 311and the vial 308 is fixed such in the second recess 312 that they have apredetermined distance from each other (see FIG. 32). For example thefirst recess 311 and the second recess 312 each may comprise at leastone web or similar projection at its inner surface which forms a snapconnection with the housing 301 of the syringe and/or the needle boot315 or which forms a snap connection with the vial 308, for example atits neck section (see FIG. 32). If the syringe 300 and the vial 308 arefixed within the supporting unit 310 and both parts 310 a and 310 b ofthe supporting unit 310 are connected to each other, a self-supportingassembly is formed which locks the pre-filled syringe 300 and the vial308 in position, for example, during transit and storage, preventingthem from making contact with each other.

The vial 308 comprises a seal 313 which covers the vial 308 at its frontend of the neck. The seal 313 closes the second chamber 309hermetically.

The drive unit 370 of the base station 350 comprises for example a firstmotor and a second motor. Additionally, an optional high frequencytransducer 371 as a vibrating unit and further an optional heaterelement 372 are provided within the housing 351 of the base station 350.The base station 350 further comprises a recess 365 at the upper side ofthe housing 351 which is adapted to receive and releasably fix theassembly comprising the syringe 300, and the vial 308 when locked withinthe supporting unit 310. Therefore the recess 365 at least partlycorresponds to the outer circumference of the assembly.

In order to reconstitute a drug and to prepare the syringe 300 forinjection the assembly shown in FIG. 32 comprising the syringe 310, thesupporting unit 310 and the vial 308 is inserted into the recess 365 ofthe base station 350 by the user and fixed there. The syringe 300 withthe needle 302 and the vial 308 is now in the initial position. The basestation 350 has the following interfaces to the assembly shown in FIG.32:

-   -   the vial, 308, is held stationary;    -   the syringe 300 engages, for example with its housing 301, with        a first linear slide 374 that is actuated in an axial direction        by a motor drive unit 370;    -   and plunger 307 engages with a second linear slide 375 that is        actuated in an axial direction by a second, independent, motor        drive unit (not shown).

The fixing of the assembly of FIG. 32 may be achieved either through:

-   -   passive clips, which the user can overcome to pull the assembly        out; or,    -   a separate motor drive unit can operate a clamping mechanism to        hold the assembly in place during the reconstitution process;        or,    -   the assembly shown in FIG. 32 can only engage/disengage with the        first and second linear slides when they are in their initial        positions.

In operation, in the position in which the assembly of FIG. 32 isinserted, that assembly may have to pass through slots in housing 351that align with the first and second linear slides. Once the drive unitshave begun to move, features on the assembly no longer align with theslots in housing 351, and the user cannot remove the assemblyprematurely. Thereby, the assembly is held at an angle in the basestation 350 with the vial 308 positioned higher than the syringe 300 sothat second component from the second chamber 309 of the vial 308 ratherthan air is drawn into the syringe 300 during preparation. This isrealized by the tilting angle of the recess 365 of the base station 300with regard to the opposite platform face 366 on which the base station350 stands. The base station 350 contains a feature to unlock the partsof the supporting unit 310 allowing the syringe housing 301 and the vial308 to move relative to each other when positioned within the recess 365of the base station 350. For example, this unlock feature may consist ofa flexible hook element inside supporting unit 310 which locks into afeature on the syringe housing 301, so that the two parts cannot moverelative to each other. A pin feature in recess 365 may penetrate asmall hole in supporting unit 310, to push the flexible hook element outof the way, enabling housing 301 to move relative to supporting unit310. Alternatively, rather than being a fixed pin, this unlock featurecould be actively driven, e.g. with a solenoid. The feature shouldremain unlocked as the assembly is removed from the base station 350, sothat the user can withdraw the syringe 300 for injection.

In the next step the first motor of the drive unit 370 drives thehousing 301 of the syringe 300 towards the vial 308 by means of thefirst slide 374. The needle boot 315 is compressed against the vial 308and the needle 302 is inserted into the seal 313 of the vial 308 forminga fluid connection with the second chamber 309 of the vial 308. Thesyringe 300 with the needle 302 is moved toward the vial 308 andinserted into the second chamber 309 for a pre-defined distance. At thesame time the second motor of the drive unit 370 moves the syringeplunger 307 by means of the second slide 375 towards the vial 308 at thesame rate so that the volume inside the first chamber 305 staysunchanged during this step. The vial 308 and the syringe 300 with theneedle 302 are now in an activated position.

In the next step, after the activated position of vial 308 and syringe300 is reached, with the first motor held stationary, the second motordrives the syringe plunger 307 towards the vial 308 by means of thesecond slide 375, expelling the first drug component, for example thediluent, into the second chamber 309 of the vial 308 forming a mixtureof the first drug component and the second drug component within thesecond chamber 309.

A range of mechanisms can be used to convert the rotational motion ofthe drive units 370 into a linear action on housing 301 of syringe 300and plunger 307. The unit shown in FIG. 30 comprises a lead screw, wherethe motor of drive unit 370 turns a threaded bar. There is a nut runningon the threaded bar, which is fixed both rotationally and axially to thefirst linear slide 374 that engages with housing 301 of syringe 300. Asthe threaded bar is rotated, the nut is driven along the threaded bar,driving housing 301 in an axial direction. The same may be provided bythe second linear slide 375 coupled to plunger 307. Alternatively, thethreaded bar can be fixed rotationally and axially to the profiledcomponent engaging with 301 or 307, and the nut is driven rotationallyby the motor. This nut can form part of the motor itself.

Once all first fluid drug component has been transferred into the secondchamber 309, the transducer 371 may agitate the vial 308 containing themixture of the first drug component and the second drug component,promoting mixing of, for example, the drug powder and the diluent. Thistransducer 371 may be a piezoelectric transducer, i.e. a piece ofpiezoelectric ceramic between two electrodes. If an oscillating voltageis applied to the electrodes, the thickness of the transduceroscillates, creating a pressure wave. Due to the inherently smalldisplacements of piezoelectric transducers, very good acoustic couplingis necessary between the transducer 371 and the vial 308. This is likelyto require at least a spring-loaded contact between the transducer andthe vial, or even a liquid- or gel-based coupling. Alternatively, thetransducer 371 may be an electromagnetic linear actuator, such as avoice coil or a solenoid. This operates at lower frequency, but thelarger displacements achievable mean that it is simpler to transmit theagitation into the mixture. Alternatively, a motor driving an imbalancedload (a vibration motor) could be used to generate the oscillatingpressure waves. At the same time or afterwards, the heater element 372may heat up the mixture to a pre-set temperature, for example in therange of 18° C. to 26° C., reducing the likelihood that a cold mixturecauses discomfort during drug injection into the patient. The heaterelement 372 may be a simple resistive element, generating heat when anelectric current passes through. A thermistor (temperature measurementsensor) would be necessary to ensure that it is not overheated, unlessthe system is designed so that it is physically impossible for any faultto lead to overheating. Alternatively, heat can be supplied through asolid-state heat pump, i.e. a Peltier device.

Once the second drug component is fully dissolved in the first drugcomponent or the other way around forming a reconstitution or once bothcomponents are mixed and—if applicable—the reconstitution or mixturereaches the correct temperature, the second motor drives the syringeplunger 307 by means of the second slide 375 into axial direction awayfrom the vial 308 drawing the mixture or reconstitution into the syringe300, namely from the second chamber 309 of the vial 308 into the firstchamber 305 of the syringe 300. Since the vial 308 is positioned higherthan the syringe 300, and the needle 302 is at the lowest point of thevial 308, the base station ensures that only the mixture orreconstitution of the second chamber 309 has drawn into the syringe 300,minimizing the air volume in the syringe 300. In the next step the firstmotor and the second motor of the drive unit 370 act together to pullthe syringe 300 and with it the needle 302 out from the vial 308. Theuser then takes the syringe 300 out from the recess 365 of the basestation 350, removes the supporting unit 310 from the syringe andmanually injects the reconstituted or mixed drug contained in the firstchamber 305 of the syringe 300. The vial 308 is a disposable device,wherein the syringe 300 may be a disposable or reusable device.

The embodiment of a drug mixing or reconstitution system shown in FIGS.33 to 37 is similar to the embodiment shown in FIGS. 29 to 32 but withan autoinjector 400 instead of the syringe 300. An element of thisembodiment of the system having the same last two digits of thereference number but a leading digit 4 instead of 3 corresponds to therespective element of the system shown in FIGS. 29 to 32.

The autoinjector 400 may be a traditional spring driven design or onethat is actuated by a fluid, for example, air pressure. In thefollowing, certain aspects are explained by means of an autoinjector 400actuated by air pressure which is provided to users with atmosphericpressure in an air chamber 414 initially. Certain aspects of theinvention work similarly with an autoinjector using a spring as the drugdelivery energy source.

The drug reconstitution system comprises the autoinjector 400, a vial408 and a supporting unit 410 which comprises two parts 410 a and 410 bfor connecting to each other and fixing the autoinjector 400 and thevial 408 within forming an assembly for transit and storage in apre-defined distance or relative position to each other. Additionally, abase station 450 is provided.

The autoinjector 400 further comprises a first chamber 405 and a needle402. The first chamber 405 contains a first drug component, for examplea diluent. The vial 408 comprises a second chamber 409 containing asecond drug component, for example a lyophilized drug, and a seal 413covering the vial and closing its second chamber 409 hermetically. Thesystem comprises further a needle boot 415.

For reconstitution or mixing of the first and second drug components ofthe autoinjector 400 and the vial 408 the needle boot 415 is attached toa first recess 411 of the supporting unit 410 as shown in FIG. 36. Then,the assembly is composed by connecting the first and second part 410 a,410 b of the supporting unit 410 to each other and inserting the vial408 and the autoinjector 400 into their respective first and secondrecess 411, 412. For attachment of the autoinjector 400 to thesupporting unit 410 a needle guard 417 of the autoinjector 400 has to beretracted in order to expose the needle 402 which is then covered by theneedle boot 415 (see FIG. 35). The autoinjector 400 and the vial 408 arefixed to the supporting unit 410 for example by a snap connection.

In order to reconstitute a drug with the system shown in FIGS. 33 to 37the assembly (see FIG. 35) is inserted into a recess 465 of the basestation 450 as shown in FIG. 33. Now the autoinjector 400 and the vial408 are in an initial position. A feature on the base station 450unlocks the parts 410 a, 410 b of the supporting unit 410, allowing theautoinjector 400 with the needle boot 415 and the vial 408 to movetowards each other along an axial direction of the autoinjector 400 bymeans of a first slide connected to the drive unit 470. For example, theunlock feature may consist of a flexible hook element projecting fromthe inner surface of the supporting unit 410 which locks into arespective recess on outer surface of the autoinjector housing 401, sothat the supporting unit 410 and the autoinjector housing 401 cannotmove relative to each other. A pin feature in recess 465 may penetrate asmall through hole in supporting unit 410 when correctly attached to thebase station 450 within the recess 465, to push the flexible hookelement out of the way, enabling autoinjector housing 401 to moverelative to the supporting unit 410. Alternatively, rather than being afixed pin, this unlock feature could be actively driven, e.g. with asolenoid, or a second drive motor. Alternatively, instead of activatinga release mechanism inside supporting unit 410, the unlock feature couldfully open supporting unit 410 up, i.e. separate the two parts 410 a,410 b of the autoinjector housing. The unlock feature should remainunlocked as the assembly is removed from the base station 450, so thatthe user can withdraw the syringe 400 for injection.

In the next step, a needle of the base station 450 pierces a septum 418at the autoinjector body 401, allowing an air pump 473 of the basestation 450 to pump air in and out an autoinjector air chamber 414comprising the plunger 407. The needle is fluidly connected to the airpump 473. Then, a first motor of a drive unit 470 of the base station450 pushes the autoinjector 400 towards the vial 408. Thereby the needleguard 417 retracts further into the autoinjector body 401 and the needleboot 415 is compressed so that the needle 402 is inserted into the vial408, e.g. its second chamber 409, through the seal 413 for exampleformed as a rubber cap. The first slide connected with the drive unit470 engages with a feature on housing 401, and drives it axially. Arange of mechanisms can be used to convert the rotational motion of thedrive unit motor into a linear action on the autoinjector body 401. Themechanism shown in FIG. 37 is a lead screw, where the motor turns athreaded bar. There is a nut running on the threaded bar, which is fixedboth rotationally and axially to a first linear slide (e.g. a profiledcomponent) that engages with the autoinjector body 401. As the threadedbar is rotated, the slide is driven along the threaded bar, drivingautoinjector body 401 in an axial direction towards the vial 408 therebyinserting the needle 402 into the second chamber 409. The autoinjector400 and the vial 408 are now in an activated position.

Afterwards, a second motor of the drive unit 470 of the base station 450activates a mechanism of the autoinjector 400 to unlock a plunger 407 ofthe autoinjector 400 allowing the plunger 407 to move using a plungerlocking mechanism 420. The locking mechanism 420 exists so that once theautoinjector 400 is filled and primed, it does not release its storedenergy and inject drug until it is activated by the user. It is shown inFIG. 35 as a simple locking pin, but it can be any catch feature thatlocks the plunger in position. This catch is later released to initiatedrug delivery, e.g. the user presses a button to move the catch awayfrom the plunger, or the catch is released when the needle guard ispressed against the skin. However, it must also be operated by the basestation 450, in order that the base station 450 can perform mixing andpriming of the autoinjector 400. Therefore, second motor of the driveunit 470 releases the autoinjector plunger 407, for example by releasingthe catch of the locking mechanism 420. Then, driven by the drive unit470, the air pump 473 of the base station 450 pumps air into the airchamber 414 surrounding the plunger 407 via the needle which pierces theseptum 418 thereby pushing the plunger 407 towards the vial 408 to expelthe first drug component from the first chamber 405 at the same time.Accordingly, the first drug component of the first chamber 405 can nowbe mixed and/or reconstituted within the second chamber 409 of the vial408 with the second drug component.

For mixing and/or reconstituting, the base station 450 may vibrate thevial 408 at a high frequency using a transducer 471 (vibrating unit)and/or warm up the mixture within the vial 408 at the same time using aheater element 472. Once the mixture or reconstitution is prepared, theair pump 473 of the base station 450 works in reverse to pump air out ofthe air chamber 414 generating a vacuum in order to pull the plunger 407away from the vial 408 such that the drug mixture or reconstitution isdrawn into the first chamber 405 of the autoinjector 400. In the nextstep the second motor of the drive unit 470 activates the plungerlocking mechanism 420 to lock the plunger 407 in position again. Now,the air pump 473 pumps compressed air into the air chamber 414, thistime as the drug delivery power source. Then the first motor draws theautoinjector 400 out of the vial 408, allowing the user to remove theassembly 410 from the base station 450.

In order to use the autoinjector 400, the user pulls to remove the vial408 and the supporting unit 410 by opening the two parts 410 a, 410 b.This also removes the needle boot 415 from the autoinjector 400 in thesame step. Removal of the needle boot 415 has the additional advantagethat it removes the chance of injecting rubber debris from the needleboot 415 into the patient. This step also reveals the needle guard 417(see FIG. 36). Then, the user presses the needle guard 417 onto theinjection site, pushing the needle guard 417 into the autoinjector body401 and inserting the needle 402 into the patient. A feature of theneedle guard 417 activates the mechanism of the autoinjector 400 tounlock the plunger 407. In one embodiment of the unlock mechanism thereis an axial extension of needle guard 417 towards the locking mechanism420. As the needle guard 417 is pushed back into housing 401, thisextension engages with a ramp or similar mating feature in lockingmechanism 420, moving it out of the plunger 407 or otherwise disengagingthe locking mechanism. The plunger 407 then moves towards the needle 402under air pressure thereby providing injection of the mixture orreconstitution into the patient. Once the injection is finished, theuser removes the autoinjector 400 from the injection site and the needleguard 417 extends outwards under a spring force of a spring 419 to coverthe needle 402 again. The needle guard 417 also locks itself against theautoinjector body 401 to prevent needle 402 stick injuries.

In an alternative embodiment of the above explained autoinjector conceptactuated by air pressure an autoinjector concept using a spring as thedrug delivery energy source can be used. The method is basically thesame except for during the mixing and/or reconstitution stage the secondmotor of the drive unit 470 actuates the plunger 407 to expel the firstdrug component into the second chamber 409 of the vial 408. After mixingor reconstitution, the second motor withdraws the plunger 407, producingan underpressure within the first chamber 405 and drawing the mixed orreconstituted drug into the autoinjector 400, namely its first chamber405. Completion of this movement happens when the plunger 407 reachesits locking position at the proximal end, wherein this action maycompress a delivery spring ready for drug delivery at the same time.Activation happens analogously to the above embodiment, when the userpresses the needle guard 417 onto the injection site, pushing the needleguard 417 into the autoinjector body 401, inserting the needle 402 intothe patient and unlocking the plunger 407, allowing the spring to drivethe plunger 407 downwards to expel the drug from the first chamber 405.Although the above example states compressing the delivery spring whendrawing the drug back into the autoinjector 400 it is also possible forthe spring to be compressed during manufacturing.

In a further alternative embodiment the mixture comprising the firstdrug component and the second drug component can be transferred back andforth between the first chamber 305, 405 of the autoinjector or syringeand the second chamber 309, 409 of the vial 308, 408. Thereby, therespective needle 302, 402 preferably creates water jet during transfer,promoting mixing or reconstitution.

Before the user injects the mixed or reconstituted drug the user mayprime the syringe 300 manually. In another embodiment instead of primingthe syringe 300 manually, the base station can be provided with arespective feature to prime the syringe 300. This can be done, forexample, by using the second drive mechanism which axially moves theplunger 307 a small distance, whilst holding housing 301 still, so thatany air in the syringe is expelled. The same applies to the autoinjector400, wherein the autoinjector may either be powered by air pressure or aconventional mechanical spring.

The main advantage of the above described drug reconstitution systemwith a base station 350, 450, a syringe 300 or autoinjector 400, asupporting unit 310, 410 and a vial 308, 408 consists therein, that itautomates the reconstitution operation, thereby removing all manualsteps. If a transducer 371, 471 is provided in the base station 350, 450it improves the consistency and repeatability of reconstitution. Thesystem further reduces the number of devices presented to the user andremoves the need to disinfect the drug vial 308, 408. Additionally, itreduces the chance of injecting air into the patient. With regard to theautoinjector version, wherein the base station 450 primes theautoinjector 400 right before use there is the advantage that thisallows the autoinjector 400 to be stored and transported without stress,reducing the complexity of the autoinjector 400 and the risk of misfireand failure.

REFERENCE NUMBERS

100, 200, 300, 500 syringe

101, 201, 301, 351, 501, 510 a housing

101 a ratchet

101 b return track

102, 202, 302, 402, 502 needle

105, 205, 305, 405, 505 first chamber

107, 207, 307, 407, 507 plunger

107 a clip member

108 distal end section

109, 209, 309, 409, 509 second chamber

111, 511 lower piston

112, 512 upper piston

112 a clip member

113 handle

114 through hole

115, 315, 415 needle boot

117 cotter pin

120 rib

122 needle

125 membrane

210 slug-like element

210 a distal end

210 b proximal end

211, 313, 413 seal

213 arrow

214 arrow

215 needle cover

220 element

250, 350, 450 base station

260 electromagnetic unit

260 a electromagnetic coil

260 b steel pole piece

262 line of magnetic field

265 opening

270 control unit

275 button

308, 408 vial

310, 410 supporting unit

310 a, 310 b, 410 a, 410 b part of supporting unit

311, 411 first recess

312, 412 second recess

365, 465, 511 a recess

366, 466 platform face

370, 470 drive unit

371, 471 transducer

372, 472 heater element

374 first linear slide

375 second linear slide

400 autoinjector

401 autoinjector body

414 air chamber

417 needle guard

418 septum

419 spring

420 locking mechanism

473 air pump

513 projection

530 compression spring

535 cap

536 clip mechanism

538 O-ring

540, 541, 542 arrow

1-7. (canceled)
 8. A device comprising: a housing; a first chamberwithin the housing, wherein the first chamber contains a first material;a second chamber containing a first piston and a second piston, whereinthe first piston and the second piston are axially moveable within thesecond chamber; and a second material initially contained within thesecond chamber between the first piston and the second piston, whereinthe device is adapted such that activation of the device causes movementone of the first piston or the second piston in an axial direction ofthe device thereby moving the other of the first piston and the secondpiston in the axial direction of the device, opening a fluidcommunication path between the second chamber and the first chamber, andexpelling the second material from the second chamber into the firstchamber via the fluid communication path, and wherein the device furthercomprises a plunger which closes a proximal end of the first chamberwithin the housing, wherein the plunger contains the second chamber,wherein the plunger is axially moveable within the housing of thedevice, and wherein axial movement of the plunger within the housingactivates the device and causes a pressure drop in the first chamber. 9.The device of claim 8, wherein the plunger further comprises athrough-hole at its distal end closed by a plug which is connected withthe second piston.
 10. The device of claim 9, wherein at least one of aninner surface of the plunger or an outer surface of the plug comprisesweb-like elements dimensioned such that after activation of the deviceby pulling the plunger, the pressure drop in the first chamber causesthe second piston to move in a distal direction relative to the plunger.11. The device of claim 10, wherein the web-like elements are configuredto, in response to the second piston moving in the distal directionrelative to the plunger, counteract with the plug and/or the innersurface of the plunger thereby creating the fluid communication pathbetween the second chamber and the first chamber and expelling thesecond material into the first chamber.
 12. The device of claim 11,wherein the inner surface of the plunger comprises an inner surface ofthe through-hole of the plunger.
 13. The device of claim 11, wherein theplunger comprises a handle at its proximal end.
 14. The device of claim11, wherein the plug comprises a set of longitudinal ribs at its outersurface.
 15. The device of claim 8, wherein the second material isdriven into the first chamber by a high speed jet.
 16. The device ofclaim 8, wherein the first material is a fluid or a solid material, andthe second fluid material is a diluent.
 17. The device of claim 8,wherein the first piston and the second piston close a proximal end anda distal end of the second chamber, respectively.
 18. The device ofclaim 17, wherein the first piston and the second piston are configuredsuch that movement of one of the first piston or the second pistondrives movement of the other of the first piston or the second pistonvia pressure transfer through the second material.
 19. The device ofclaim 8, wherein opening the fluid communication path between the secondchamber and the first chamber causes the pressure drop in the firstchamber to cause a pressure drop in the second chamber.
 20. A method formixing and/or reconstituting a first material in a first chamber of adevice with a second material in a second chamber of the device, themethod comprising: after activation of the device, moving one of a firstpiston in a second chamber or a second piston in the second chamber inan axial direction of the device; moving the other of the first pistonand the second piston in the axial direction of the device; opening afluid communication path between the second chamber and the firstchamber; and expelling the second material into the first chamber suchthat the second material mixes and/or reconstitutes with the firstmaterial, wherein the activation of the device is facilitated by axiallymoving a plunger of the device within a housing of the device and causesa pressure drop in the first chamber, wherein the plunger closes aproximal end of the first chamber within the housing and contains thesecond chamber.
 21. The method of claim 20, wherein opening the fluidcommunication path between the second chamber and the first chambercomprises causing an axial movement of the second piston to force a plugconnected with the second piston to move through a through-hole within adistal end of the plunger.
 22. The method of claim 20, furthercomprising causing the activation of the device, wherein causing theactivation of the device comprises pulling the plunger in a proximaldirection.
 23. The method of claim 20, wherein expelling the secondmaterial into the first chamber comprises driving the second materialinto the first chamber by a high speed jet.
 24. The method of claim 20,wherein the first material is a fluid or a solid material, and thesecond material is a diluent.
 25. The method of claim 20, wherein thefirst piston and the second piston close a proximal end and a distal endof the second chamber, respectively.
 26. The method of claim 20,wherein: moving the one of the first piston or the second piston in theaxial direction of the device comprises causing a pressure transferthrough the second material, and moving the other of the first pistonand the second piston in the axial direction of the device comprisesmoving the other of the first piston and the second piston in the axialdirection in response to the pressure transfer through the secondmaterial.
 27. The method of claim 20, wherein opening the fluidcommunication path between the second chamber and the first chambercomprises causing the pressure drop in the first chamber to cause apressure drop in the second chamber.